ZZ-3K3A-301: A multicenter, randomized, placebo-controlled, double-blinded, Phase 3 study to evaluate the efficacy and safety of 3K3A-APC (RHAPSODY-2)

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Stroke is a leading cause of adult disability in America, and one of the leading causes of death in the world. If patients arrive at a hospital soon after their stroke begins, recanalization with thrombolytic therapy and thrombectomy can be very effective. Not all patients respond to recanalization with a complete cure, however, so new, effective adjunctive treatments for stroke are needed. In designing adjunctive therapy, it is important to consider that the brain consists of many different types of cells (e.g., neurons, glia, and endothelial cells among others), and during stroke, the brain loses 1.2 million neurons per minute. That is to say, “time is brain”. For decades, adjunctive treatments have been tested for benefit in stroke patients but failed partly because the candidate treatment may have been given too late, and partly because they protected only the neurons, ignoring the other important types of cells in the brain. Another significant reason for previous failure is that prior trials did not require recanalization simultaneous with the administration of the candidate therapy. Thanks to the wider use of thrombectomy—after which the occluded brain artery is documented to be open—it is now possible to test candidate stroke treatments under the best possible circumstances. We now propose a drug that powerfully protects neurons, glia, and endothelial cells in the brain. This drug, 3K3A-APC, acts on cells to induce protection by several mechanisms. Multiple laboratories—using neurobehavioral and histomorphometric endpoints in several animal models—have shown that 3K3A-APC powerfully reduces the effects of experimental stroke, even when administered up to 4 hours after the stroke begins. In human volunteers, only mild and moderate side effects were detected at clinically relevant doses. In stroke patients who received thrombolytic treatment or thrombectomy or both, 3K3A-APC was well tolerated and appeared to reduce cerebral bleeding. In the current proposal, we seek to establish a safe, effective dose of 3K3A-APC and proceed to a definitive efficacy trial to determine whether 3K3A-APC improves 3-month outcome after stroke. We also seek to show whether 3K3A-APC reduces early bleeding associated with recanalization therapy. If this trial is successful, 3K3A-APC treatment will significantly improve stroke therapy by augmenting the beneficial effects of recanalization, reducing the associated bleeding, and reassuring more physicians to prescribe recanalization without fear of bleeding complications.